Case 2 DR IRENE SCHEIMBERG, CONSULTANT PAEDIATRIC & PERINATAL - PowerPoint PPT Presentation

Case 2 DR IRENE SCHEIMBERG, CONSULTANT PAEDIATRIC & PERINATAL PATHOLOGIST THE ROYAL LONDON HOSPITAL, BARTS HEALTH NHS TRUST, LONDON, UK

Clinical history  Mother primigravida, high BMI  Normal antenatal scans  Reduced fetal movements 48h before delivery at 40+4 weeks  Caesarean section due to profound & prolonged bradycardia  Male 4kg born in poor condition  HR 80bpm, spontaneous breathing at 6 minutes, O 2 sats 80%  Cooling but he developed severe HIE  PPHN & diffuse cardiac hypertrophy  Intensive care withdrawn on day 2

Current case Range for GA Best fit Gestation 40 40 41 Birth weight 4002 2472-3372 2425-3625 Body weight 4213 2472-3372 2425-3626 Crown-heel 55.2 43.6-53.0 43.5- 53.3 Crown- rump 39 32.4-38.0 32.9-39.1 Toe-heel 8.5 6.9-8.5 7.1-8.7 Organs Current case Range for GA Range for BW Femur 7.9 7.2-7.8 7.2-7.9   Heart 32.5 14.8 - 26 21.1 - 31.9 Lung: BW Humerus 7 6.3-7.0 6.3-7.1 R. Lung 62.1 - - 0.027 Head circ. 34 33-37 33.5-37.5 L. Lung 51.1 - - Weights in g; measurements in cm   (combined) 113.2 21.9 - 67.3 47 - 84.6 N>0.015 for< 28wks   Liver 136.2 92.1 - 163.7 148 - 220 N>0.012 for> 28wks   Pancreas 6.0 2.3 - 4.9 3.1 - 6.3   Spleen 15.8 7.1 - 13.7 10.5 - 16.3 Brain: liver Thymus 6.0 4.5 - 14.5 7.8 - 15.2 2.7 R. Kidney 25.7 - - Normal = 3 L. Kidney 27.3 - - (combined) 53 15.8 - 38.8 24.9 - 45.1 Fetus: placenta Adrenals 8.0 4.7 - 10.7 6.7 - 14.1 NA Brain 368 277 - 435 357 - 461   Placenta NA 390 - 643 - Weights in g

Heart

Histology coronary arteries

Carotid artery and branches

Infarct in papillary muscle AV node

Lungs

Descending aorta and renal arteries

Adrenals and pancreas

Kidney and liver

Brain CD68

Diagnosis Generalized idiopathic arterial calcification of infancy (GACI)

GACI  Rare autosomal recessive disorder  Diffuse calcification with hydroxyapatite deposits in the media’s elastic lamina of large and medium sized arteries associated with intimal proliferation arterial stenosis  Antenatal USS may show hydrops and calcification (from 18/40)  Depending on severity infants may present with IUD, NN heart failure, arterial hypertension and death within the first 6 months of life in 60-80%  Spontaneous regression and survival to adulthood  Biphosphonates (synthetic analogs of pyrophosphate) block conversion of Ca+ into hydroxyapatite & calcifications disappear  ENPP1 enzyme replacement therapy successful in mice (2018)

Genetics  70%: Several inactivating mutations of the ENPP1 gene which encodes ectonucleotide pyrophosphatase/phosphodiesterase 1 (PP1), a potent calcification inhibitor  30%: inactivating mutations of ABCC6 gene encoding an ATP-binding efflux transporter responsible for PXE (pseudoxanthoma elasticum)  AR hypophosphatemic rickets may also be associated with inactivation mutations of ENPP1 & may alleviate symptoms of GACI

GACI and PXE  PXE: multisystemic ectopic mineralization disorder, late onset, progressive clinical manifestations in skin, eyes and CV system  Genotypic overlap between PXE and GACI  Several families with GACI have ABCC6 mutations. In one family one sibling died of GACI and another develop PXE 25 years later  Recent study: 92 GACI patients  3 patients treated with biphosphonates presented later with clinical features of PXE had ENPP1 mutations  14 patients (of 28 with no disease causing ENPP1 mutation) had ABCC6 mutations

Mechanism of mineralization ABCC6 mediates ATP release from  hepatocytes to the extra cellular space where ATP is converted into Ppi and AMP by ENPP1 CD73 converts AMP to Pi & adenosine  (inhibitor of tissue nonspecific alkaline phosphatase (TNAP) which hydrolyzes Ppi to Pi Deficiencies in ABCC6, ENPP1 and  CD73 lead to reduce plasma PPi levels and PPi/Pi ratios therefore promoting hydroxyapatite mineralization in peripheral tissues

Spectrum of the disease

Thank you With thanks to Mo Haini

References Chong CR, Hutchins GM. Idiopathic infantile arterial calcification:: The spectrum of clinical  presentations. Ped Develop Pathol 11:405:415; 2008 Mastrolia SA, Weintraub AY, Baron J et al. Antenatal diagnosis of idiopathic arterial  calcification: a systematic review with a report of two cases. Arch Gynecol Obstet 291:977- 986; 2015 Nitschke Y, Baujat G, Botschen et al. Generalized arterial calcification of infancy and  pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6 . Am J Med Gentics 90:25-39; 2012 Lorenz-Depiereux B, Schanbel D, Tiosano D, Hausler G, Strom TM. Loss of function ENPP1  mutations cause both generalized arterial calcification of infancy and autosomal recessive hypophosphatemic rickets. Am J Med Gentics 86:267-272; 2010 Uitto J, Li Q, van de Wetering K, Varadi A, Terry SF. Insights into pathomechanisms and  treatment development in heritable ectopic mineralization disorders: summary of the PXE International Biennial Research Symposium-2016. J Invest Dermatol 137:790-795; 2017 Ali SA, Ng C, Votava-Smith JK, Randolph LM, Pitukcheewanont P. Biphosphonate therapy in  an infant with generalized arterial calcification and ABCC6 mutation. Osteopor Int 2018, Sep 11 [Epub ahead of print] Khan T, Sinkevicious KW, Vong S et al. ENPP1 enzyme replacement therapy improves blood  pressure and cardiovascular function in a mouse model of generalized arterial calcification of infancy (GACI). Dis Model Mech. 2018 Sep 3 [Epub ahead of print]